A Review of Paclitaxel and Novel Formulations Including Those Suitable for Use in Dogs

INTRODUCTION

Department:

Chest cancer, the nearly mutual malignancy in women, continues to be a major wellness business organisation. Almost one third of all cancers in women are breast cancer, and the affliction is expected to kill an estimated 40,110 women in the U.s.a. in 2004.¹ Treatments for early-stage illness have improved survival, and improvements in chemotherapies accept shown demonstrable do good for women with metastatic breast cancer (MBC).^2,3

Paclitaxel plays a central role in the treatment of MBC.^iv However, its utilise is limited by its poor solubility and the toxicities associated with Cremophor EL (polyethoxylated castor oil), the lipid-based solvent used as a vehicle for Taxol (Bristol-Myers Squibb Co, Princeton, NJ) and its generic equivalents. Polyethoxylated brush oil leaches plasticizers from standard intravenous (IV) tubing and has been associated with histamine release, severe anaphylaxis, hyperlipidemia, abnormal lipoprotein patterns, aggregation of erythrocytes, and prolonged, sometimes irreversible sensory neuropathy.^5-seven Every bit a result, the administration of paclitaxel requires a big book of IV fluid, a long infusion period (1 to 24 hours), special 4-infusion sets, in-line filters, and premedication with steroids and antihistamines to minimize the risk of hypersensitivity reactions.⁴ Despite these precautions, astringent and even fatal hypersensitivity reactions still occur.^viii In improver, polyethoxylated castor oil forms micelles in the plasma compartment that entrap paclitaxel, resulting in nonlinear pharmacokinetics for paclitaxel.⁹

ABI-007 (Abraxane; American BioScience Inc, Santa Monica, CA) is a polyethoxylated castor oil-free, albumin-bound paclitaxel that has been developed to address these limitations. This novel approach delivers paclitaxel every bit a intermission of albumin particles (boilerplate size, approximately 130 nm) in saline that allows for a shorter infusion duration (thirty minutes) without special delivery appliance and without steroid and antihistamine premedication for hypersensitivity reactions. The use of albumin equally the delivery vehicle for paclitaxel has the potential to enhance drug transport into tumors by taking advantage of albumin receptor (gp60)-mediated transcytosis across endothelial cells.¹⁰

A phase I report of ABI-007, administered Iv over 30 minutes every 3 weeks, established 300 mg/m² as the maximum-tolerated dose (MTD),^eleven notably college than the MTD for paclitaxel with the three-calendar week regimen (175 mg/g²). Dose-limiting toxicities were keratitis, blurred vision, sensory neuropathy, stomatitis, and grade 4 neutropenia. No severe hypersensitivity reactions were observed despite the absence of premedication. Maximum paclitaxel concentration (C_max) and area under the concentration-time curve from fourth dimension goose egg to infinity (AUC_0-∞) increased linearly for the ABI-007 dose range of 135 to 300 mg/grand² administered over 30 minutes. C_max and AUC_0-∞ values for individual patients correlated well with toxicity.

The phase II study reported hither explored the efficacy and safety of ABI-007 at the MTD of 300 mg/m² in patients with MBC. The chief finish signal was tumor response rate. Secondary objectives were to evaluate time to disease progression (TTP), changes in quality of life from baseline, and survival and to assess the antitumor activity of ABI-007 monotherapy in anthracycline-naive versus anthracycline-exposed patients.

PATIENTS AND METHODS

Department:

The protocol and all related materials were canonical by local institutional review boards or ethics committees. The study was conducted in compliance with Good Clinical Practice, guidelines of the International Conference on Harmonisation, and the Declaration of Helsinki. Written informed consent was required from all patients earlier participation. Case-report forms were submitted to the sponsor (American BioScience Inc), who reconciled the drug accountability logs with the patients enrolled at each site.

Patient Population

Nonpregnant women (≥ 18 years of historic period) were eligible for inclusion in the study. Patients had histologically or cytologically confirmed chest cancer (measurable bidimensionally) with prove of recurrence or metastasis merely no other malignancy except nonmelanoma skin cancer, cervical intraepithelial neoplasia, or in situ cervical cancer. Patients had expected survival of > 8 weeks with adequate hematologic, hepatic, and renal function. Patients were excluded from participation if they had clinical bear witness of encephalon metastasis; serious concurrent illness; an Eastern Cooperative Oncology Group operation status of ≥ 2; sensory neuropathy grade ≥ 1; or received taxane chemotherapy within the previous 6 months, any other investigational drug within the previous iv weeks, or anthracycline therapy inside the previous three weeks. In that location were no restrictions on enrollment based on the number of prior chemotherapy regimens.

Handling

ABI-007 was administered on an outpatient basis via 30-minute 4 infusion at 300 mg/thou² (paclitaxel dose) without steroid or antihistamine premedication, granulocyte colony-stimulating factor support, specialized 4-infusion sets, or in-line filtration. Handling was repeated every three weeks until affliction progression or unacceptable toxicity occurred. Dose reductions of 25% of the original dose (from 300 to 225 mg/mⁱⁱ) were required for grade 4 hematologic toxicity, neutropenic fever or sepsis, or grade 3 or 4 nonhematologic toxicity. If any of these adverse events (AEs) recurred after initial resolution and reinitiation of ABI-007 dosing, a 2d dose reduction to 50% of the initial dose was recommended for all subsequent cycles. Patients who experienced an additional recurrence of the dose-limiting AEs were withdrawn from the study.

Assessments

Target lesions were measured bidimensionally at baseline, at the end of every other chemotherapy cycle, and within 2 weeks of study discontinuation. The imaging method used for a given tumor at baseline was used consistently for that tumor throughout the report. Imaging for tumor reevaluation was express to sites of preexisting metastasis identified at baseline or to new sites suspected to contain metastasis.

Target-lesion-response analyses were based on investigator evaluation of radiologically and clinically detected target lesions. Tumor responses were categorized according to WHO guidelines¹²: consummate response (CR) was the disappearance of all clinical evidence of visible tumor; partial response (PR) was a ≥ l% decrease in product of largest perpendicular diameters of measurable lesions; stable affliction was not meeting the criteria for response or progressive disease; and progressive disease was unequivocal increment in size of any assessable, measurable lesion or appearance of a new lesion. Responses to handling were confirmed by restaging ≥ iv weeks after the initial documentation of response for CR and PR and ≥ 8 weeks for stable disease. Survival was assessed on a monthly basis for 3 months afterward report completion and every iii months thereafter.

AEs were coded by using the Medical Dictionary for Drug Regulatory Affairs and further classified co-ordinate to National Cancer Institute Mutual Toxicity Criteria. Considering ocular toxicities were reported every bit dose-limiting toxicities in the phase I written report, ophthalmologic examinations were conducted at baseline and later every two treatment cycles.

Statistical Methods

The primary efficacy end point was the percentage of patients in the intent-to-treat population who achieved a confirmed CR or PR. The study design incorporated Simon's optimal two-phase procedure for phase II clinical trials,¹³ which included an interim review of response rate after the first 12 enrolled patients had completed two treatment cycles. The treatment was to exist considered a failure and the written report terminated if one or less patient had achieved a CR or PR at this time. In contrast, the treatment was to exist considered promising and additional patients were enrolled if ii or more patients had achieved a CR or PR at this time. The success/failure criteria for the study were based on response rates of 30% to forty% for paclitaxel⁴ and some other widely used taxane, docetaxel (Taxotere; Aventis Pharmaceuticals, Inc, Bridgewater, NJ),¹⁴ in anthracycline-treated patients with breast cancer. Based on these reports, a 30% target-lesion-response rate for ABI-007 monotherapy was considered a treatment success for this assessment, and a response rate ≤ 10% was considered a failure. All patients who received at least one dose of ABI-007 were included in the response and toxicity analyses. Fourth dimension to commencement response, TTP, and survival were summarized by using Kaplan-Meier methods.¹⁵

RESULTS

Section:

Betwixt October 1999 and May 2001, 63 patients were enrolled at vii sites (4 in India, three in the Usa). All patients were included in the safety and efficacy analyses. Baseline and disease characteristics are listed in Table 1. Eleven patients (17%) had been treated previously with taxanes: three in the adjuvant setting and eight for metastatic disease. Patients received a median of half-dozen cycles of ABI-007 treatment (Tables 2 and 3); 16 patients (25%) had dose reductions, primarily considering of hematologic toxicities (see Safety). Of the dosing cycles that were delayed (21 of 321 [7%]), nearly were delayed four to 8 days.

Efficacy

Antitumor activity was noted with an overall response rate of 48% (95% CI, 35.three% to 60.0%; Table iv) and was the same regardless of whether WHO or Response Evaluation Criteria in Solid Tumors criteria were used. Complete responses were reported in two patients, and partial responses were reported in 28 patients. Maximum confirmed responses were observed most often at cycles 2 and 4. Response rates were higher among patients who had not received prior treatment for metastatic affliction: 64% for patients who received ABI-007 as first-line therapy, compared with 21% for patients with prior chemotherapy for metastatic affliction. Responses likewise were higher in patients with no prior exposure to anthracyclines compared with those who had been treated with anthracyclines (58% five 41%, respectively). The response rate for patients with dominant lesion sites that were visceral was xl%, whereas the response rate for those with nonvisceral lesions was 68%.

Median TTP was 26.6 weeks for all patients and 48.1 weeks for responding patients (confirmed CR or PR). Median overall survival was 63.6 weeks. The median Eastern Cooperative Oncology Grouping performance status and the Global Health Status (EORTC QLQ-C30) scores did non change from baseline to the concluding evaluation.

Safety

The most frequently reported toxicities were those expected for paclitaxel in this patient population. Handling-related toxicities of whatsoever grade that occurred in > 20% of patients were alopecia, anemia, neutropenia, leukopenia, sensory neuropathy, fatigue, nausea, myalgia, infection, vomiting, and stomatitis/pharyngitis (Fig 1 ). Treatment-related grade 3 and iv toxicities are listed in Table v. Form iv neutropenia occurred in 24% of patients, primarily during the first treatment cycle, and was managed with dose reduction; febrile neutropenia occurred in three of these patients. Grade three neutropenia was noted in 27% of patients. Neutropenia generally was transient, asymptomatic, and isolated.

Class 2 and 3 sensory neuropathy occurred in 12 (nineteen%) and seven (xi%) patients, respectively; no grade 4 neuropathy was reported. Episodes of myalgia typically were worse immediately after dosing, generally resolved before the next dosing, and did non result in premature discontinuation of treatment. No episodes of grade 4 myalgia were reported. No severe hypersensitivity reactions were noted despite the absence of premedication with steroids or antihistamines. Ocular/visual toxicities, which were dose-limiting toxicities in the phase I written report, were noted in fifteen patients (24%) and were mostly dry eye (eight patients) and blurred vision (half dozen patients); no grade three or 4 events were noted. Fluid retention and nail changes were noted in 3 and two patients, respectively; no grade 3 or 4 events were noted.

Seven patients (xi%) discontinued treatment prematurely because of AEs: 5 for sensory neuropathy (treatment related), one for extremity pain (unlikely related to written report drug), and one for massive aspiration into the lung (unrelated to treatment). Sixteen patients (25%) required dose reductions for toxicities; toxicities resulting in a dose reduction for two or more than patients were uncomplicated neutropenia (seven patients), sensory neuropathy (four patients), delirious neutropenia (three patients), myalgia (3 patients), and fatigue (2 patients).

Of the 321 treatment cycles administered, 21 (7%) were delayed in half-dozen patients to let resolution of toxicities (neutropenia and urticaria; thrombocytopenia; thrombocytopenia and jaundice; sensory neuropathy; fever; blurred vision). I patient died as a result of mayhap handling-related cardiac ischemia/infarction, and i patient died every bit a outcome of massive aspiration into the lung (unrelated to handling).

DISCUSSION

Section:

Preclinical studies demonstrated that penetration of paclitaxel into tumors was greater with ABI-007 than with solvent-based paclitaxel, resulting in superior antitumor activity for ABI-007 in athymic mice with homo chest cancer.^16,17 This stage Ii written report confirmed that ABI-007 has significant antitumor activity in patients with MBC. The use of albumin equally the carrier rather than polyethoxylated brush oil allows for doses of paclitaxel much higher than those achievable with paclitaxel and avoids the toxicities associated with synthetic solvents, as evidenced by the lack of hypersensitivity reactions in the absence of corticosteroid and antihistamine premedication. This albumin-based particle composition of paclitaxel is the first biologically interactive grade of the drug with the potential to exploit a receptor-mediated pathway, allowing increased send of albumin-bound paclitaxel from claret to tumor.^xviii

The overall response rate (CR + PR) for ABI-007 at 300 mg/m^two on an every-three-weeks regimen was 48%. It is well recognized that patient selection can strongly influence the response rates seen in phase Ii trials. Notwithstanding, our data compare favorably with response rates reported for paclitaxel 250 mg/m² administered as a 3-hour infusion (22% to 44%)^19-21 or as a 24-hour infusion (54% to 62%).^21-23 Of note is the high response charge per unit (64%) in patients who received ABI-007 as first-line therapy for their metastatic disease. By comparison, phase III trials with other taxanes as first-line therapy established response rates to paclitaxel 175 or 200 mg/m^two of 26%²⁴ and 25%,²⁵ respectively, and 48% for Taxotere 100 mg/thou².²⁶ In preclinical models, ABI-007 demonstrated greater antitumor activity than paclitaxel.²⁷ These preclinical data and the demonstrated activity of ABI-007 in this trial were the footing for a randomized, comparative trial of ABI-007 versus paclitaxel in MBC.²⁸

ABI-007-associated adverse effects were less frequent and less severe than would be expected for comparable doses of paclitaxel. In this written report of ABI-007 at a dose of 300 mg/m², the incidence of grades 3 and 4 neutropenia combined was 51%. In contrast, in a stage III study of paclitaxel 250 mg/m², this incidence was 73% when administered every bit a 3-hr infusion and 81% when administered as a 24-hour infusion.²¹ Similarly, the incidence of grade 4 neutropenia in this study was 24%, which is less than half of the 57% seen in a phase III written report of 250 mg/m² paclitaxel¹⁹ and is comparable with the 28% incidence observed for the standard 175 mg/1000ⁱⁱ dose of paclitaxel.⁴ The relatively low incidences of grade four neutropenia and related complications seen in this study are also striking in comparison with those noted for docetaxel; grade four neutropenia, neutropenic sepsis, and septic deaths occurred in 84%, 12%, and 1.5% of patients with MBC treated with a standard 100 mg/m² dose of docetaxel, respectively.¹⁴ Similarly, the eleven% incidence of grade iii sensory neuropathy in this study at a dose of 300 mg/one thousand² compares favorably with that reported for paclitaxel 250 mg/m² administered as a three-hour (26% and 22%)^19,21 or 24-hr (13%) infusion.²¹

Ocular toxicities (superficial keratopathy and blurred vision) were dose limiting in the phase I trial of ABI-007 at doses of 375 mg/m², but severe ocular events were not observed in the current report despite careful ophthalmologic monitoring. The lack of astringent ocular toxicity suggests that this toxicity either occurred by take a chance in the stage I study or was dose related and therefore problematic only when ABI-007 was administered at doses above the MTD. It has been reported that ocular disturbances were noted with paclitaxel administration at paclitaxel doses of 175 and 225 mg/thou² as a direct issue of the drug itself.²⁹ Other mutual AEs seen in this study (eg, nausea, airsickness, fatigue, arthralgia, myalgia, alopecia) are well-recognized, taxane-associated toxicities and were usually self-limited or hands managed by using standard approaches. Nail changes and fluid retention were uncommon.

ABI-007 was initially developed to avoid the toxicities associated with polyethoxylated castor oil that limit the paclitaxel dose that may be administered safely. In preclinical studies, ABI-007 could be administered at a paclitaxel dose approximately 50% college than paclitaxel and did not effect in hypersensitivity reactions. Consistent with these findings, the stage I trial of ABI-007¹¹ showed that the MTD of ABI-007 administered every 3 weeks with a 30-infinitesimal infusion was 300 mg/1000^two, approximately lxx% college than that of paclitaxel.⁴ Hypersensitivity reactions did not occur despite the absence of corticosteroid and antihistamine premedication, and administration occurred over xxx minutes without specialized IV-infusion sets or in-line filters. The stage II written report reported here further confirms the advantages of removing polyethoxylated castor oil. In addition, the relatively low incidence of neutropenic toxicities supports the suggestion that polyethoxylated castor oil increases the myelosuppression of chemotherapeutic agents that are MDR1 substrates (eg, paclitaxel) by inhibiting the MDR1 gene product (p-glycoprotein) in hematopoietic cells.³⁰

The pregnant antitumor action of ABI-007 and favorable rubber profile may be related not only to the absence of polyethylated brush oil simply too to the choice of albumin as the formulation vehicle. Albumin is the natural carrier of lipophilic molecules (eg, paclitaxel) in humans. Albumin-bound macromolecules are actively transported across microvascular endothelial cells (transcytosis) and into tumor tissues via a specific pathway that is activated by albumin bounden to its specific receptor, gp60 (too known as albondin). Binding of albumin to gp60 on the endothelial-jail cell membrane triggers the formation of vesicles (caveolae) to initiate the transcytosis pathway.^31,32 The master regulator of signaling molecules in caveolae seems to be caveolin-i,³³ which shows elevated expression in a variety of neoplasms including breast,³⁴ lung,³⁵ and prostate cancer.³⁴ Transcytosis of paclitaxel is inhibited by polyethoxylated castor oil.¹⁸ ABI-007, a polyethoxylated castor oil-gratis, albumin-jump paclitaxel, thus may optimize drug delivery to tumors via receptor-activated transcytosis in improver to exploiting other differences between tumor and normal tissues such as the increased neovasculature, capillary leakage, and decreased/absent lymphatic drainage that are associated with enhanced penetration and retentivity of albumin-bound paclitaxel in tumor tissue. This hypothesis is supported by preclinical data showing preferential tumor targeting with ABI-007: selectively increased intratumor paclitaxel levels were achieved with ABI-007 compared with paclitaxel in creature models of breast cancer.¹⁸ Higher intratumor drug concentrations would be expected to consequence in college efficacy. Indeed, preliminary results of an ongoing phase Iii trial in women with MBC comparing every-3-weeks regimens of 260 mg/m² ABI-007 to 175 mg/yard² paclitaxel indicates that ABI-007 has efficacy superior to that of paclitaxel as assessed by tumor response rate and TTP.²⁸

Although additional clinical trials are required to ascertain the role of ABI-007 in the handling of breast cancer, the written report reported here demonstrates that paclitaxel administered in a matrix of albumin without solvents has significant antitumor action with a favorable safety contour. ABI-007, a novel conception of albumin-bound paclitaxel, may offer patients a number of advantages over existing taxanes. No premedication with corticosteroids, prolonged infusions, or special IV-infusion sets are required with ABI-007, thereby facilitating drug assistants and improving patient acceptance. ABI-007 allows for doses of paclitaxel higher than those doable with paclitaxel without compromising patients' quality of life. The relatively low incidence of neutropenia makes ABI-007 a candidate for combinations with other chemotherapeutic agents or for use in dose-dense handling regimens.

Authors' Disclosures of Potential Conflicts of Interest

Department:

Although all authors completed the disclosure proclamation, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not beingness evaluated equally part of the investigation. For a detailed description of the disclosure categories, or for more information virtually ASCO'southward disharmonize of interest policy, please refer to the Author Disclosure Announcement and the Disclosures of Potential Conflicts of Interest department in Information for Contributors.

Authors	Employment	Leadership	Consultant	Stock	Honoraria	Research Funds	Testimony	Other
Nuhad 1000. Ibrahim						American Bioscience (C)
Brian Samuels			American Bioscience (A)	American Bioscience (A)	American Bioscience (A)
Ray Page						American Bioscience (B)
Dinesh Doval						American Bioscience (B)
Kirtikumar M. Patel						American Bioscience (B)
Paul Bhar	American Bioscience Inc			American Bioscience Inc (B)
Neil Desai	American Bioscience Inc			American Pharmaceutical Partners (B)

Section:

Fig 1. Handling-related toxicities/agin events reported in > 20% of patients. Hematologic toxicities were based on laboratory values; others were based on adverse-issue reports from the clinical investigators. ANC, absolute neutrophil count.

Table 1. Baseline and Disease Characteristics

Tabular array 2. Treatment Exposure

Table 3. Treatment Exposure by Cycle and Dose

Table four. Response Rates

Table five. Handling-Related Grade 3 and 4 Toxicities/Adverse Events (North = 63)

© 2005 by American Guild of Clinical Oncology

Sponsored by American BioScience, Inc, Santa Monica, CA.

Presented in part at the 25th Annual San Antonio Chest Cancer Symposium, San Antonio, TX, December 11–fourteen, 2002; and the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18–21, 2002.

Authors' disclosures of potential conflicts of interest are institute at the end of this commodity.

We admit Susan A. Thomas and Aaron Van Etten for assistance in preparing this manuscript.

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Source: https://ascopubs.org/doi/10.1200/JCO.2005.11.013

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